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Macrocyclic inhibitors of hepatitis C virus NS3-serine protease

a hepatitis c virus and macrocyclic inhibitor technology, applied in the direction of cyclic peptide ingredients, drug compositions, peptides, etc., can solve the problems of low sustained response rate of therapies, frequent side effects, and poor treatment progress of patients with hcv infection

Inactive Publication Date: 2005-06-02
MERCK SHARP & DOHME CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0798] The obtained Ki values for the various macrocycles of the present invention are given in Tables 1, 2 and 2A, where the compounds have been arranged in the order of ranges of Ki* values, as well as in Table 3. From these test results, it would be apparent to the skilled artisan that the compounds of the invention have excellent utility as NS3-serine protease inhibitors.

Problems solved by technology

The prognosis for patients suffering from HCV infection is currently poor.
HCV infection is more difficult to treat than other forms of hepatitis due to the lack of immunity or remission associated with HCV infection.
These therapies suffer from a low sustained response rate and frequent side effects.
Currently, no vaccine is available for HCV infection.

Method used

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  • Macrocyclic inhibitors of hepatitis C virus NS3-serine protease

Examples

Experimental program
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Effect test

example 1

PREPARATIVE EXAMPLE 1

[0342]

[0343] The synthesis of 1b can be accomplished using the procedure of (1) Myers, A. G.; Gleason, J. L.; Yoon, T.; Kung, D. W.; J. Am. Chem. Soc 1997, 119, 656; (2) Myers, A. G.; Schnider, P.; Kwon, S.; Kung, D. W.; J. Org. Chem., 1999, 64, 3322.; or (3) Myers, A. G.; Gleason, J. L.; Org. Synth. 1998, 76, 57.

[0344] A solution of amine 1a (24 g, 120 mmol) in THF (300 mL) was treated with anhydrous LiCl (16.80 g, 400 mmol) over 0.5 h and stirred till the reaction mixture turns homogeneous. The reaction mixture was cooled to 0° C. and treated with a THF solution of LiHMDS (66.80 g, 400 mmol in 300 ml of THF) over 20 min. The reaction mixture was stirred at 0° C. for 0.5 h and treated with 6-bromohexene (19.44 g, 120 mmol) and stirred at rt. for 24 h. The reaction mixture was dissolved in aq. 1 M HCl and concentrated in vacuo to remove THF. The mostly aq. layer was further diluted with 3M aq HCl (300 mL) and extracted with ether (2×200 mL). The aqueous layer w...

example 2

PREPARATIVE EXAMPLE 2

[0365]

[0366] A solution of alcohol 1i (1.1 g, 2.25 mmol) in methanol (30 mL) was treated with Pd / C (10% w / w, 100 mg) and hydrogenated at 60 psi for 3 h. The reaction mixture was filtered through a plug of celite, concentrated in vacuo to yield 2a which was used in the next step without further purification.

[0367] Crude 2a from step A was oxidized using Dess-Martin reagent (1.14 g, 2.68 mmol) following the procedure similar to step H (preparative example 1) to yield 2b (760 mg) as a colorless foam.

[0368] MS (ESI), m / z, relative intensity 1005 [(2M+Na)+, 10], 530 [(M+K)+, 20], 514 [(M+Na)+, 90], 492 [(M+1)+, 30], 436 (40), 392 (100).

[0369] Compound 2b (200 mg, 0.41 mmol) from step B was converted to 2c (250 mg) using CH3COOH (60 mg) and methylisocyanoacetate (99 mg, 1 mmol) following the procedure similar to step I (preparative example 1) as a mixture of diastereomers.

[0370]1H NMR (CDCl3, 300 MHz, mixture of diastereomers) 8.05, 7.93 (d, 1H), 6.60 (d, 1H, J=...

example 3

PREPARATIVE EXAMPLE 3

[0375]

[0376] A solution of 2 (40 mg, 0.0053 mmol) in HCOOH (2 mL) was stirred at rt. for 2 h and concentrated in vacuo. The residue was repeatedly dissolved in toluene and dried in vacuo to remove residual formic acid. The residue was dissolved in CH2Cl2 / DMF (1 mL each) and treated with tBuNCO (10 μL) and NMM (15 μL) at 0° C. and left in the refrigerator for 12 h. The reaction mixture was concentrated in vacuo and purified by chromatography (SiO2, acetone / hexanes 1:2) to yield 3 (21 mg) as a colorless solid.

[0377] MS (ESI), m / z, relative intensity 774 [(M+Na)+, 50], 752 [(M+1)+, 70], 653 (90), 420 (30), 297 (30), 148 (100), 134 (40).

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Abstract

The present invention discloses novel compounds which have HCV protease inhibitory activity as well as pharmaceutical compositions comprising such compounds and methods of using them to treat disorders associated with the HCV protease. The novel compounds typically include a 15-20 member macrocycle and have the general structure of structural Formula 1: wherein Z′, L′, M′, R1, X and D are defined herein.

Description

FIELD OF INVENTION [0001] The present invention relates to novel hepatitis C virus (“HCV”) protease inhibitors, pharmaceutical compositions containing one or more such inhibitors, methods of preparing such inhibitors and methods of using such inhibitors to treat hepatitis C and related disorders. This invention additionally discloses novel macrocyclic compounds as inhibitors of the HCV NS3 / NS4a serine protease. This application claims priority from U.S. provisional patent application Ser. No. 60 / 506,637 filed Sep. 26, 2003. BACKGROUND OF THE INVENTION [0002] Hepatitis C virus (HCV) is a (+)-sense single-stranded RNA virus that has been implicated as the major causative agent in non-A, non-B hepatitis (NANBH), particularly in blood-associated NANBH (BB-NANBH) (see, International Patent Application Publication No. WO 89 / 04669, equal to US 2003162167). NANBH is to be distinguished from other types of viral-induced liver disease, such as hepatitis A virus (HAV), hepatitis B virus (HBV),...

Claims

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Application Information

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IPC IPC(8): A61K31/33A61K38/00A61K38/12A61K38/21C07D245/04C07D401/12C07D403/12C07D409/12C07D487/04C07D513/04C07K5/02C07K5/08
CPCA61K31/33A61K38/12A61K38/21A61K38/212C04B35/632C07D245/04C07D401/12C07D403/12C07D409/12C07D487/04C07D513/04C07K5/0217C07K5/0802A61P1/16A61P31/12A61P31/14A61P43/00A61K2300/00
Inventor VENKATRAMAN, SRIKANTHNJOROGE, F.WU, WANLIGIRIJAVALLABHAN, VIYYOORMCKITTRICK, BRIANSU, JINGVELAZQUEZ, FRANCISCOPINTO, PATRICK
Owner MERCK SHARP & DOHME CORP
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